The incidence of Alzheimer's disease is expected to increase through the year 2050 with an estimated prevalence of 11 to 16 million cases. Currently, two classes of medications are FDA approved for managing symptoms of Alzheimer's disease—acetylcholinesterase inhibitors (AChEIs) and an N-methyl-D-aspartase (NMDA) receptor antagonist. AChEIs are commonly used as initial treatment on diagnosis. The AChEIs—donepezil, rivastigmine, galantamine, and tacrine—are indicated for mild-to-moderate Alzheimer's disease; only donepezil is approved for the severe stage.
AChEIs do not help everyone who has Alzheimer's disease and in fact are not efficacious in many patients. Considering that AChEIs and memantine have only a modest symptomatic effect, and cannot prevent Alzheimer's disease decline and slow disease progression, there is a high unmet need for more effective symptomatic treatments and for a disease modifying/slowing therapies.
The use of selective 5-HT6 receptor antagonists to treat cognitive dysfunction has been suggested and is based on several lines of reasoning. For example, selective 5-HT6 receptor antagonists have been shown to modulate cholinergic and glutamatergic neuronal function. The activity of selective 5-HT6 receptor antagonists has been demonstrated in animal models of cognitive function. Since the disclosure of the first selective 5-HT6 receptor antagonists, there have been several reports on the activity of these selective compounds in in-vivo models of cognitive function. N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine, CAS number 467458-02-2, (herein also referred to as “Lu AE58054”) is a 5-HT6 receptor antagonist and its chemical structure is depicted below:

The synthesis of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine, its use for the treatment of Alzheimer's disease, and pharmaceutical compositions comprising this compound are disclosed in U.S. Pat. No. 7,157,488 (“the '488 patent”). The '488 patent further describes the preparation of the hydrochloride salt of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine.
N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine can be produced according to the method described in WO 11/76212.
By using the methods in the '488 patent and in WO 11/76212, the N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is obtained as a solid.
Pharmaceutical solids can exist in amorphous, glass or crystalline states. Furthermore crystalline materials can be found as hydrates or other solvates. If such a compound can exist in more than one crystalline arrangement (polymorphic form) the compound is said to show polymorphism.
In order to be able to provide an active pharmaceutical ingredient of high and reproducible quality and with well-defined biological activity, it is desirable to have the active pharmaceutical ingredient in the most thermodynamically stable form.
The inventors of the present invention have found a new and thermodynamically stable form of the hydrochloride salt of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine.